Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, TN, 37830, USA.
Bone Res. 2023 Oct 26;11(1):57. doi: 10.1038/s41413-023-00295-4.
Molecular mechanisms transducing physical forces in the bone microenvironment to regulate bone mass are poorly understood. Here, we used mouse genetics, mechanical loading, and pharmacological approaches to test the possibility that polycystin-1 and Wwtr1 have interdependent mechanosensing functions in osteoblasts. We created and compared the skeletal phenotypes of control Pkd1;Wwtr1, Pkd1, Wwtr1, and Pkd1/Wwtr1 mice to investigate genetic interactions. Consistent with an interaction between polycystins and Wwtr1 in bone in vivo, Pkd1/Wwtr1 mice exhibited greater reductions of BMD and periosteal MAR than either Wwtr1 or Pkd1 mice. Micro-CT 3D image analysis indicated that the reduction in bone mass was due to greater loss in both trabecular bone volume and cortical bone thickness in Pkd1/Wwtr1 mice compared to either Pkd1 or Wwtr1 mice. Pkd1/Wwtr1 mice also displayed additive reductions in mechanosensing and osteogenic gene expression profiles in bone compared to Pkd1 or Wwtr1 mice. Moreover, we found that Pkd1/Wwtr1 mice exhibited impaired responses to tibia mechanical loading in vivo and attenuation of load-induced mechanosensing gene expression compared to control mice. Finally, control mice treated with a small molecule mechanomimetic, MS2 that activates the polycystin complex resulted in marked increases in femoral BMD and periosteal MAR compared to vehicle control. In contrast, Pkd1/Wwtr1 mice were resistant to the anabolic effects of MS2. These findings suggest that PC1 and Wwtr1 form an anabolic mechanotransduction signaling complex that mediates mechanical loading responses and serves as a potential novel therapeutic target for treating osteoporosis.
骨微环境中物理力转导调节骨量的分子机制尚未完全阐明。在这里，我们使用小鼠遗传学、机械加载和药理学方法来测试多囊蛋白-1 (PC1) 和 Wwtr1 在成骨细胞中是否具有相互依赖的机械感知功能。我们创建并比较了对照 Pkd1;Wwtr1、Pkd1、Wwtr1 和 Pkd1/Wwtr1 小鼠的骨骼表型，以研究遗传相互作用。与体内骨中多囊蛋白和 Wwtr1 之间存在相互作用一致，Pkd1/Wwtr1 小鼠的 BMD 和骨外膜 MAR 降低幅度大于 Wwtr1 或 Pkd1 小鼠。微 CT 3D 图像分析表明，与 Pkd1 或 Wwtr1 小鼠相比，Pkd1/Wwtr1 小鼠的骨量减少是由于小梁骨体积和皮质骨厚度的丢失更大。与 Pkd1 或 Wwtr1 小鼠相比，Pkd1/Wwtr1 小鼠的骨机械敏感和成骨基因表达谱也表现出相加性降低。此外，我们发现与对照小鼠相比，Pkd1/Wwtr1 小鼠在体内胫骨机械加载和负荷诱导的机械敏感基因表达方面表现出受损的反应。最后，与载体对照相比，用激活多囊蛋白复合物的小分子机械模拟物 MS2 治疗的对照小鼠导致股骨 BMD 和骨外膜 MAR 显著增加。相比之下，Pkd1/Wwtr1 小鼠对 MS2 的合成代谢作用具有抗性。这些发现表明 PC1 和 Wwtr1 形成一个合成代谢机械转导信号复合物，介导机械加载反应，并可能成为治疗骨质疏松症的潜在新治疗靶点。
